Selective inhibition of anti‐MAG IgM autoantibody binding to myelin by an antigen‐specific glycopolymer

Autor: Pinelopi Tsouni, Shahram Attarian, Andreas J. Steck, Beat Ernst, Delphine Demeestere, Thierry Kuntzer, Butrint Aliu, Ruben Herrendorff, Marie Théaudin, Emilie Seydoux, Pascal Hänggi, Tobias Derfuss, Emilien Delmont, Alexandre Brodovitch, Thomas Oberholzer, José Boucraut
Přispěvatelé: Assistance Publique - Hôpitaux de Marseille (APHM), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
HIGHLIGHTED ARTICLE
demyelinating peripheral neuropathy
Biochemistry
Peripheral blood mononuclear cell
Epitope
03 medical and health sciences
Cellular and Molecular Neuroscience
Myelin
0302 clinical medicine
medicine
anti‐MAG IgM autoantibodies
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
myelin‐associated glycoprotein
Myelin-associated glycoprotein
Neuroinflammation & Neuroimmunology
Chemistry
[SCCO.NEUR]Cognitive science/Neuroscience
Autoantibody
anti-MAG IgM autoantibodies
antigen-specific treatment
monoclonal gammopathy of neurological significance
myelin-associated glycoprotein
medicine.disease
Molecular biology
antigen‐specific treatment
030104 developmental biology
Peripheral neuropathy
medicine.anatomical_structure
nervous system
Original Article
ORIGINAL ARTICLES
Glycoprotein
030217 neurology & neurosurgery
Ex vivo
Zdroj: Journal of Neurochemistry
Journal of Neurochemistry, 2020, 154 (5), pp.486-501. ⟨10.1111/jnc.15021⟩
Journal of neurochemistry, vol. 154, no. 5, pp. 486-501
ISSN: 0022-3042
1471-4159
DOI: 10.1111/jnc.15021⟩
Popis: Anti‐myelin‐associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural killer‐1 (HNK‐1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3‐O‐sulfo‐β‐d‐glucopyranuronate)‐(1→3)‐β‐d‐galactopyranoside (PPSGG) in selectively neutralizing anti‐MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti‐MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK‐1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti‐MAG IgM to peripheral nerves. The polymer selectively bound anti‐MAG IgM autoantibodies and prevented the binding of patients’ anti‐MAG IgM antibodies to myelin of non‐human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK‐1 epitope removed anti‐MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B‐cell depletion with anti‐CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen‐specific treatment of anti‐MAG neuropathy. Read the Editorial Highlight for this article on page 465.
Anti‐MAG (myelin‐associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the HNK‐1 (human natural killer‐1) epitope. This glycoepitope is highly expressed on adhesion molecules such as MAG and is localized mainly in paranodal loops and Schmidt–Lantermann incisures of the peripheral nervous system. The glycopolymer PPSGG selectively bound anti‐MAG IgM autoantibodies and prevented the binding of patients’ autoantibodies to myelin of primate sciatic nerves in the IFA (indirect fluorescents assay) anti‐MAG IgM assay (right panel). These findings corroborate the therapeutic potential of PPSGG for an antigen‐specific treatment of anti‐MAG neuropathy. Read the Editorial Highlight for this article on page 465.
Databáze: OpenAIRE
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